Summary/Abstract Data from 2015 show that American Indian/Alaska Natives (AI/AN) have the highest rates of diagnosis for opioid use disorders (OUD) and deaths from drug overdose. Of particular concern is the prevalence rate of opioid use among emerging adults (ages 18?25) as this is a developmental period of heightened vulnerability and critical social, neurological, and psychological development. This proposal responds to RFA-DA-19-035, HEAL initiative: Preventing OUD in Older Adolescents and Young Adults (ages 16-30) by developing and implementing a culturally-centered intervention to address opioid misuse among urban AI/AN emerging adults (EAs) in California: POMANAYA (Preventing Opioid Misuse Among Native American Young Adults). This proposal builds on our previous work over the past decade working closely with urban AI/AN communities across California to develop culturally-appropriate programming to address alcohol and other drug (AOD) use. The proposed project also builds off our team?s work identifying how social networks affect risk behaviors among vulnerable populations. We propose a multi-tiered intervention approach that will include intervening at the individual level (POMANAYA) and at the community level: wellness gatherings (WG). For the UG3 Phase, we plan to conduct focus groups with EAs, parents of EAs, AI/AN providers, and our Elder Advisory Board in urban communities throughout California to understand how to a) best identify, reach, and engage AI/AN EAs to access programming addressing opioid use, b) adapt and enhance our existing culturally-sensitive prevention intervention program, Motivational Interviewing and Culture for Urban Native American Youth (MICUNAY), for AI/AN EAs to address social network factors that amplify (or reduce) opioid and AOD use risk, and c) pilot test POMANAYA to ensure feasibility and acceptability of the program. For the UH3 phase, our aims are to 1) Compare AI/AN EAs who receive POMANAYA+WG (n=185) to AI/AN EAs who receive opioid education (n=185) on outcomes at 3, 6, and 12 months, 2) explore potential mechanisms of change for decreases in opioid and AOD use outcomes through mediation analyses, focusing on changes in social networks and cultural connectedness, 3) develop and test strategies to facilitate sustainability of POMANAYA within these communities through key informant interviews and focus groups, and 4) conduct an economic evaluation to quantify programmatic costs and cost-effectiveness of the multi-tiered intervention approach, relative to opioid education. Results from this study could significantly advance scientific knowledge and clinical practice for AI/AN emerging adults.